Antiretroviral therapy (ART) has revolutionized the management of human immunodeficiency virus (HIV) infection, transforming what was once a rapidly progressing, fatal illness into a manageable chronic condition. These powerful medications effectively suppress viral replication, allowing individuals to live long and healthy lives with an undetectable viral load. Despite this profound success in controlling the virus, a complete elimination of HIV from the body remains an ongoing challenge. The virus possesses a unique ability to persist within the body, even when treatment is consistently maintained.
Defining the HIV Reservoir
The HIV reservoir is a small population of infected cells, primarily resting memory CD4+ T cells, that allows HIV to persist. These cells harbor the virus in a latent state, with its genetic material (proviral DNA) integrated directly into the host cell’s DNA.
In this latent state, the virus is not actively producing new viral particles or proteins. Because the virus is not actively replicating, these cells appear normal to the immune system and are unaffected by current antiretroviral medications. This latent reservoir can last many years, up to 25 years.
Formation and Location of Reservoirs
HIV reservoirs establish early in infection, often within days or weeks of initial exposure, even before antiretroviral therapy begins. During this acute phase, HIV infects various immune cells, and a subset transition into a resting state while carrying the integrated viral DNA.
Latently infected cells reside in specific sanctuary sites. Lymphoid tissues, such as lymph nodes, the spleen, and gut-associated lymphoid tissue (GALT), are major locations for these reservoirs due to their high concentration of immune cells. Other sites, including the brain and bone marrow, can also harbor these viral populations.
The Barrier to a Cure
The existence of this latent reservoir presents the primary obstacle to achieving a cure for HIV. Because the virus in these reservoir cells is not actively replicating or producing proteins, they are “invisible” to the immune system. This allows the virus to evade natural immune responses.
Current antiretroviral drugs are designed to target specific steps in the viral replication cycle, such as entry into cells or the production of new viral copies. Since the virus in the reservoir is dormant, these medications have no effect on the latently infected cells. If an individual discontinues ART, the virus in these reservoir cells can reactivate. This reactivation leads to a rapid rebound of the virus in the blood, causing disease progression and requiring lifelong treatment to resume.
Strategies for Eradication
Scientists are exploring several strategies to eliminate the HIV reservoir and achieve a lasting cure. One approach is known as “Shock and Kill,” which aims to reactivate the latent virus and then clear the infected cells. This involves using drugs, called latency-reversing agents (LRAs), to reactivate the dormant virus, forcing it to begin replication and produce viral proteins. Once reactivated, these cells become visible and susceptible to clearance by the immune system or intensified antiretroviral therapy.
Conversely, the “Block and Lock” strategy seeks to achieve a functional cure by permanently silencing the latent virus. This approach uses latency-promoting agents (LPAs) or other compounds to reinforce the dormant state of the virus. By inducing permanent latency, the virus would remain suppressed even if ART were stopped, without needing to eliminate the infected cells.
Gene therapy techniques, such as CRISPR-Cas9, are being investigated to directly target the integrated HIV DNA. This technology can precisely cut the viral DNA out of the host cell’s genome. Researchers are also exploring gene editing to modify host cell receptors, like CCR5, making cells resistant to HIV infection.
Immunotherapies represent another approach, aiming to enhance the body’s ability to control or eliminate infected cells. This includes therapeutic vaccines to boost anti-HIV immune responses, and broadly neutralizing antibodies (bNAbs) that target a wide range of HIV strains to clear infected cells or prevent new infections. Chimeric antigen receptor (CAR) T-cell therapy is also being explored to engineer a patient’s own T cells to recognize and destroy HIV-infected cells.